Catalyst-free resorbable homopolymers and copolymers

ABSTRACT

The invention relates to resorbable homopolymers and copolymers which are substantially free from polymerization catalysts and processes for preparing them.

This a continuation of application Ser. No. 213,889, filed Mar. 16,1994, abandoned which is a continuation of application Ser. No. 072,897,filed Jun. 3, 1993, now abandoned, which is a continuation ofapplication Ser. No. 945,544, filed Sep. 16, 1992, now abandoned, whichis a continuation of application Ser. No. 819,306, filed Jan. 9, 1992,now abandoned, which is a continuation of application of applicationSer. No. 670,843, filed Mar. 18, 1991, now abandoned, which is acontinuation of application Ser. No. 429,667, filed Oct. 31, 1989, nowabandoned, which is a division of application Ser. No. 301,200, filedJan. 24, 1989, now U.S. Pat. No. 4,960,866, which is a continuation ofapplication Ser. No. 128,855, filed Dec. 4, 1987, now abandoned.

The invention relates to catalyst-free resorbable homopolymers andcopolymers and processes for preparing them.

In recent years, interest in the use of resorbable polyesters hasincreased sharply; for example in the field of surgery, for use asstitching material or clamps, in osteosynthesis or as active substancecarriers with a delayed controlled release of active substance. As isalready known from numerous publications, the major advantage ofresorbable polyesters, particularly those based on lactic or glycolicacid, is the fact that they are broken down completely in human oranimal tissue to form compounds which occur naturally, in the body.These breakdown products pass into the normal biochemical metabolism andare eventually metabolized to form water and carbon dioxide. Adisadvantage of the use of resorbable homopolymers and copolymers is thecatalyst content. When the polymers are resorbed, a finite quantity ofcatalyst is left behind in the tissues, since the catalyst cannot bebroken down here. Consequently irritation may occur in the tissues, anddepending on the catalyst, there is even a possibility of poisoning.Furthermore, the catalyst remaining in the homopolymer or copolymer mayalso lead to transesterification or even to the uncontrolled breakdownof the polymer and thus, for example, result in an unpredictable rate ofrelease of an active substance from a delayed-release form. Uncontrolledrelease may also lead to fracture of an implant in the case ofosteosynthesis.

Catalyst-free copolymers based on lactic and glycolic acid are known. Bydirect condensation of lactic and glycolic acid or by co-condensation ofthese two compounds it is possible to obtain low molecular weightpolymers, preferably with a molecular weight of from 2000 to 4000.Attempts at achieving high molecular weights by direct condensationhave, however, resulted in the cleavage of lactide or glycolide. Apossible cause of this is the fact that in order to separate off thewater of condensation resulting from the polyester formation, which is,in any case, only present in traces, the pressure and temperature haveto be adjusted so that the reaction conditions approximate to those oflactide or glycolide synthesis, so that there is at least somedepolymerization.

The use of strongly acidic ion exchangers for preparing a catalyst-freecopolymer from glycolide and lactide is known from European Patent 26599. Using the process described therein, it is possible to producecopolymers with a molecular weight of from 6000 up to a maximum of35000.

It is also known from European Patent Application 171 907 to preparecopolymers of lactic and glycolic acid with molecular weights of up toabout 20700 by "dehydration polycondensation".

As has been found in recent years, the use of resorbable polyesters isvery strongly linked to the chemical and physical properties of thesepolymers. By varing the composition of the comonomers, the method ofpolymerization and the choice of suitable catalysts, it was possible toprepare polymers which were suited to their intended use (e.g. stitchingmaterial, resorbable or partially resorbable osteosynthetic material,galenic preparations), but these polymers still contain finitequantities of catalyst.

Hitherto, the only catalyst-free copolymers of lactide and glycolideknown from the prior art are those having an average molecular weight ofup to 35000, at most. However, this significantly restricts their use,since in many cases it is essential to use polymers with highermolecular weights.

The invention provides resorbable homopolymers and copolymers which aresubstantially free from catalyst. Suitable polymers in accordance withthe invention are those which are soluble in an organic solvent,optionally after suitable pretreatment, e.g. tempering. Homo- andco-polymers based on hydroxycarboxylic acids, such as polymers ofglycolide, lactide, methylglycolide, dimethylglycolide,polymethylglycolide, diethylglycolide, dibutylglycolide, caprolactone,valerolactone, decolactone, propiolactone, butyrolactone andpivalolactone; polymers based on trioxane, 1,3-dioxan-2-one or1,4-dioxane, substituted 1,3-dioxan-2-one or 1,4-dioxanone,trimethylenecarbonate, ethylenecarbonate and propylenecarbonate arepreferred.

Other suitable comonomers include the following compounds: lactic acid,glycolic acid, pentaerythritol, sorbitol, adonitol, xylitol, fructose,epichlorohydrin, isopropylmorpholine, isopropylmethylmorpholinedione,β-propiolic acid, tetramethyl glycolide, β-butyrolactone,q-butyrolactone, pivalolactone, a-hydroxybutyric acid,a-hydroxyisobutyric acid, a-hydroxyvaleric acid, a-hydroxyisovalericacid, a-hydroxycaproic acid, a-hydroxyisocaproic acid,a-hydroxy-a-ethylbutyric acid, a-hydroxy-β-methylvaleric acid,a-hydroxyheptanoic acid, a-hydroxyoctanoic acid, a-hydroxydecanoic acid, a-hydroxytetradecanoic acid and a-hydroxystearic acid.

Catalyst-free homopolymers of lactide, catalyst-free copolymers ofdifferent lactides and catalyst-free copolymers of lactides andglycolide with inherent viscosities of between 0.1 and 10 dl/g areparticularly preferred.

The lactide used may be l-, d-, meso- or dl-lactide or mixtures thereof.With copolymers of glycolide and lactide, the solubility of theparticular copolymer is strongly dependent on the glycolide content.

Homopolymers of l-lactide with an inherent viscosity of 0.1 to 10 dl/gare also preferred. From the inherent viscosity, the correspondingaverage molecular weight is calculated at 2000 to 1.4 million (see. W.Dittrich and R. C. Schulz, Angew. Makro. Chem., 15 (1971) 109-126).

Also preferred are homopolymers of dl-lactide with an inherent viscosityof 0.1 to at least 5 dl/g, corresponding to average molecular weights of2000 to at least 1.5 million, calculated from the inherent viscosity byapproximation of the Staudinger index according to Solomon and Ciuta(see. J. Appl. Polym. Sci., 6.24 (1962) 683-6) and putting into theMark-Houwink equation on the parameters K=6.06×10⁻⁴ and a=0.64 (see. J.Rak, J. L. Ford, Ch. Rostron and V. Walther, Pharm. Acta Helv., 60, 5-6(1985) 162-9).

Copolymers of l-lactide and glycolide are also preferred having inherentviscosities of from greater than 1.4 to at least 4.5 dl/g (wherein, onaccount of the fact that the copolymers containing a high proportion ofglycolide begin to be insoluble, the glycolide content generally doesnot exceed 50%). Using the method described above and the Mark-Houwinkparameters K=5.45×10⁻⁴ and a=0.73 (see. S. Gogolewski and A. J.Pennings, J. Appl. Polym. Sci., 28, 1045-61) average molecular weightsof from 50000 to at least 250000 are calculated. (As used in thisspecification, the term "average molecular weight" refers to weightaverage molecular weight.)

Other preferred copolymers are those of dl-lactide and glycolide withinherent viscosities of at least 1.5 dl/g, corresponding to averagemolecular weight of at least 55000, calculated using the aboveMark-Houwink parameters for copolymers;

also copolymers of epsilon-caprolactone with l- or dl-lactide andglycolide and inherent viscosities of up to at least 4 dl/g;

also poly(l-lactide-co-dl-lactide) in the ratio 9:1,poly(l-lactide-co-glycolide) in the ratio 7:3,poly(dl-lactide-co-glycolide) in the ratio 3:1,poly(dl-lactide-co-glycolide) in the ratio 1:1,poly(dl-lactide-co-glycolide) in the ratio 45:55.

For example, homopolymers and copolymers of lactic and glycolic acid arepreferably prepared by ring-opening polymerization of the cyclicdiesters of lactic and glycolic acids, namely the lactide and glycolide.Owing to the chirality of lactic acid, the optically active l- andd-lactides and the optically inactive meso-lactide and the racemate(dl-lactide) may be included in the ring-opening polymerisation.

The conditions of this polymerization are known. A variety of compoundsmostly containing polyvalent metal ions are cited in the literature assuitable catalysts for polymerization. Tin(II) or zinc compounds arepreferably used. Of the tin compounds, tin(II) di(2-ethylhexanoate) (tinoctoate) is preferred.

The homopolymers are prepared in solution or emulsion or in a melt. Thecopolymers of any desired composition may be prepared in emulsion owingto the different reactivities of the two comonomers but are preferablyprepared by bulk polymerization in a melt. During the polymerization,the desired molecular weight and the corresponding molecular weightdistribution may be achieved by varying the reaction parameters oftemperature, time and catalyst concentration and by adding one or moreco-catalysts.

The catalyst-containing polymers prepared by known methods are dissolvedin a suitable organic solvent or in a mixture of various organicsolvents which must not be fully miscible with water. Generally, theconcentration of the dissolved polymer in the solvent should not exceed10% since otherwise the solution would become too viscous andsatisfactory processing would no longer be guaranteed. A content ofbetween 0.5 and 4.0%, particularly between 0.5 and 2.0%, is preferred.The organic solution of the homopolymer or copolymer is then broughtinto intimate contact with water, an aqueous solution of an inorganicacid, a water-soluble organic acid or a water-soluble complexing agent.After a contact time sufficient to allow the catalyst to go into theaqueous phase, the phases are separated and the organic phase containingthe catalyst-free polymer is dried. Finally, the polymer is recoveredfrom the organic phase by known methods.

Suitable solvents are those which dissolve the homopolymer or copolymerbut are immiscible or only slightly miscible with water or at least forma 2-phase system in a specific mixing ratio. Preferred solvents arehalogenated hydrocarbons such as methylene chloride or chloroform. Thesolubility of the polymers depends substantially on their compositionand can be determined by simple tests. In some cases, mixtures ofsolvents may also prove particularly suitable. In cases of polymers oflimited solubility, e.g. copolymers containing a high proportion ofglycolide, pretreatment, for example by heating or irradiation of thepolymer, is advantageous in order to increase its solubility. Suitableinorganic acids include for example hydrochloric, sulphuric orphosphoric acid, but monofunctional or polyfunctional water-solubleorganic acids such as acetic or citric acid may also be used. A suitablecomplexing agent is EDTA (ethylenediamine tetraacetate) in the form ofthe free acid or the sodium salt. The concentration of the acids orcomplexing agents used is not critical. Conveniently, a 0.1 to 5%aqueous solution, preferably 0.1 to 1% aqueous solution, is used. Ifstrongly concentrated acids are used, however, it is impossible to ruleout the possibility that the inherent viscosity of the polymer willdecrease. Processes for establishing intimate contact between the twoimmiscible phases are sufficiently well known. On a laboratory scale,simply stirring or shaking once or several times has proved completelyadequate. On an industrial scale, contact between the two immisciblephases is appropriately established by uniflow or counterflowextraction. Such processes are part of the prior art and need not beexplained in detail here. Extraction is continued or repeated until nofurther metal or metal ions can be detected in the homopolymer orcopolymer by the method of atomic absorption or any other suitableanalytical method.

After the phase separation, the organic phase is dried and thehomopolymer or copolymer is recovered, for example by a suitable methodof precipitation, and, after being dried, is characterized bymeasurement of the inherent viscosity. Suitable methods of precipitationinclude the addition of an adequate quantity of precipitation agent,preferably a low-boiling petroleum ether fraction, The inherentviscosity is measured in a suitable solvent, e.g. chloroform orhexafluoroisopropanol, at temperatures of 25° or 30° C. The term"inherent viscosity" is taken to mean the quotient of the naturallogarithm of relative viscosity and the concentration of the measuredsolution, given in [g/dl]. Using equations known from the literature, itis possible to calculate from the inherent viscosity the Staudingerindex (intrinsic viscosity) and, if the corresponding parameters areknown, using the Mark-Houwink equation, the average molecular weight.The molecular weight distribution and the polydispersity of the polymersand copolymers is preferably measured by exclusion chromatography suchas high pressure size exclusion chromatography (HPSEC) in chloroform,methylene chloride, dioxan, THF, or HFIP. Calibration is carried out: byknown methods against narrowly distributed poly(styrene) standards. Itwas established that the process according to the invention for removingthe catalyst did not adversely affect the properties of the polymer orcopolymer (e.g. expressed by the inherent viscosity).

Owing to the fact the polymers according to the invention are virtuallyfree from polymerization catalyst, they are particularly suitable forthe manufacture of objects which can be resorbed in human or animalbodies. These include, in particular, surgical stitching material,objects for use in osteosynthesis and carriers for pharmaceutical activesubstances. The latter may, for example, be in the form of tablets orcapsules but may also take the form of implantable or injectabledelayed-release forms.

The following are some typical products for medical use which mayadvantageously be made from catalyst-free polymers.

Catalyst-free products made from resorbable polymers:

    ______________________________________                                        1.    Solid products, compression moulded or machined:                              Orthopaedic pins, clamps, screws and plates,                                  clips (e.g. for vena cava),                                                   staples,                                                                      hooks, buttons and press-studs,                                               bone replacements (e.g. jaw prostheses),                                      needles,                                                                      non-permanent intrauterine inserts                                            (spermicidal),                                                                temporary drainage or exploration tubes or                                    capillaries,                                                                  surgical instruments,                                                         blood vessel implants or supports,                                            vertebrae,                                                                    extracorporeal tubes for kidney and heart-lung                                machines,                                                                     slowly disintegrating ion exchange resin,                                     slowly disintegrating products which release                                  active substances (pills, pellets),                                           reinforced bone pins, needles etc.,                                           implantable pellets, sticks, films and other                                  shaped objects charged with pharmaceutical                                    compositions for the controlled release of                                    active substance.                                                       2.    Fibre products, knitted or woven, including                                   velour                                                                        burn bandages,                                                                fracture pads,                                                                absorbent paper or swabs,                                                     medicinal dressings,                                                          items used in plastic surgery,                                                gauze, tissue, cloth, felt or sponge for                                      haemostasis,                                                                  gauze bandages,                                                               dental fillings,                                                              stitching material including ligatures.                                       Arterial transplants or replacements,                                         bandages for the surface of the skin,                                         burn dressings (combined with other polymer                                   films).                                                                 3.    Powdered products produced by spray drying,                                   grinding, precipitation or microencapsulation.                                injectable or implantable powder charged with                                 drugs for the controlled and delayed release of                               the active substance.                                                         Microporous shaped objects, films, powders and                                granules for charging with active substances.                           4.    Miscellaneous                                                                 Flakes or powders for treating burns or                                       abrasions,                                                                    foam as an absorbable prosthesis,                                             substitutes for wire in splints,                                              film spray for prosthetic elements and for the                                treatment of wounds.                                                    ______________________________________                                    

EXAMPLES Example 1 (Comparative Example)

16 g of poly(dl-lactide-co-glycolide) in a molar ratio of 1:1, with atin content of 550 ppm and an inherent viscosity of 0.37 dl/g inchloroform at 25° C. are dissolved in 80 ml of acetone at boilingtemperature, filtered and then precipitated in water. The copolymer isremoved by suction filtering, washed with cold water and dried in avacuum or circulating air drier. The tin content of the sample isdetermined by atomic absorption spectrometry and the inherent viscosityis measured in chloroform at 25° C.

Yield: 89.8% of the starting quantity Inherent viscosity: 0.40 dl/g Tincontent: 415 ppm

Example 2

100 ml batches of a 1% chloroform solution of a poly(l-lactide) with aninherent viscosity of 1.47 dl/g and a tin content of 254 ppm are stirredwith 100 ml of 0.1N hydrochloric acid for various lengths of time.

After phase separation and drying of the organic phase with sodiumsulphate the poly(l-lactide) is reprecipitated by the addition ofpetroleum ether with a boiling range of 40°-60° C. and dried in a vacuumdrying cuboard at about 40° C. until a constant weight is achieved.

The tin content of each sample is determined by atomic absorption.

    ______________________________________                                        Stirring time  tin content                                                    [minutes]      [ppm]                                                          ______________________________________                                        0              254                                                            5               29                                                            15              2                                                             ______________________________________                                    

Example 3

100 ml batches of a 1% chloroform solution of a poly(l-lactide) with aninherent viscosity of 1.47 dl/g in chloroform at 25° C. and with a tincontent of 254 ppm are stirred once, twice and three times each timewith 100 ml of a 0.1N hydrochloric acid for 5 minutes. The phases areseparated, the aqueous phases are discarded and the organic phases aredried with sodium sulphate. The poly(l-lactide) is reprecipitated by theaddition of petroleum ether with a boiling range of 40°-60° C. and driedin a vacuum drying cuboard at about 40° C. until a constant weight isachieved. The yield in each case is 85% of the starting amount.

The tin content of each sample is determined by atomic absorption.

    ______________________________________                                        Stirring time   tin content                                                   [number of times]                                                                             [ppm]                                                         ______________________________________                                        0               254                                                           1                29                                                           2                2                                                            3                2                                                            ______________________________________                                    

Example 4

100 ml of a 1% solution of a poly(l-lactide) in chloroform with aninherent viscosity of 1.47 dl/g and a tin content of 254 ppm are stirredwith 100 ml of water, or of a 1% aqueous solution of an organic acid, aninorganic acid or complexing agent for 15 minutes. The mixture is leftto stand for 10 minutes and then the phases are separated. The aqueousphase is discarded. After phase separation and drying of the organicphase with sodium sulphate, the poly(l-lactide) is reprecipitated by theaddition of petroleum ether with a boiling range of 40°-60° C. and driedin a vacuum drying cupboard at about 40° C. until a constant weight isachieved.

    ______________________________________                                        Aqueous         Yield [% of                                                                              Sn content                                         solution        material used]                                                                           [ppm]                                              ______________________________________                                        water           90         2                                                  sulphuric acid  94         2                                                  hydrochloric acid                                                                             91         2                                                  acetic acid     92         2                                                  phosphoric acid 88         2                                                  citric acid     90         2                                                  EDTA            95         2                                                  ______________________________________                                    

Example 5

100 ml batches of a 1% solution in chloroform of apoly(dl-lactide-co-glycolide) with a tin content of 550 ppm are stirredfor 15 minutes with 100 ml of a 1% hydrochloric acid solution.

After phase separation and drying of the organic phase with sodiumsulphate the copolymer is reprecipitated and dried in a vacuum dryingcupboard at about 40° C. until a constant weight is achieved.

    ______________________________________                                                       Yield [% of                                                                              Sn content                                          Molar Ratio    material used]                                                                           [ppm]                                               ______________________________________                                        50:50          99         2                                                   75:25          96         2                                                   ______________________________________                                    

What is claimed is:
 1. A resorbable polymer having a block structurecomprising a copolymer formed by ring-opening polymerization of lactideand glycolide in the presence of tin(II) catalyst, having an averagemolecular weight of at least 55,000, which is soluble in an organicsolvent and immiscible with water, which is substantially free from saidpolymerization catalyst, and having an inherent viscosity between about0.1 and 10 dl/g.
 2. A resorbable polymer having a block structurecomprising a copolymer formed by ring-opening polymerization of lactideand glycolide in the presence of tin(II) catalyst, having an averagemolecular weight of at least 55,000, which is soluble in an organicsolvent and immiscible with water, comprising no more than about 2 ppmof said polymerization catalyst, and having an inherent viscositybetween about 0.1 and 10 dl/g.
 3. An implantable, bio-resorable surgicaldevice comprising a copolymer with a block structure in accordance withclaim 1 or
 2. 4. An implantable and bio-resorable carrier for apharmaceutically active substance comprising a copolymer with a blockstructure in accordance with claim 1 or
 2. 5. A catalyst-free resorbablecopolymer having a block structure produced by the process comprisingthe steps of:(a) dissolving a catalyst-containing polymer in an organicsolvent which is immiscible with water, (b) bringing the thus dissolvedpolymer into intimate contact with water or with an aqueous phase whichcontains an inorganic acid, a water-soluble organic acid or awater-soluble complexing agent, (c) separating the organic phase fromthe aqueous phase, and (d) isolating the polymer from the organic phase.6. The resorbable copolymer, as claimed in claim 5, characterized inthat the acid or the complexing agent is present in the aqueous phase ina concentration of from about 0.1 to 5%.
 7. The resorbable copolymer, asclaimed in claims 5 or 6, characterized in that the concentration of thedissolved polymer in the organic solvent does not exceed about 10%.